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Abstract

Mycoplasma genitalium (MG) is an emerging sexually transmitted pathogen that is associated with several inflammatory syndromes including cervicitis and pelvic inflammatory disease. Despite the clinical associations of MG with inflammatory sequeale, no experimental evidence was available for the capacity to establish infection of the female reproductive tract and activate host immune responses. This considered, we undertook a multifaceted approach to understanding the capacity and mechanisms of MG to cause inflammatory reproductive tract disease using cell culture models of human epithelia and a novel murine model. In our studies, MG established a long-term intracellular infection of cultured human vaginal, ecto- and endocervical epithelial cells that resulted in pro-inflammatory cytokine secretion. We determined that a significant proportion of the inflammation was activated through ligation of highly expressed Toll-like receptors (TLR) including TLR2/6 heterodimers and TLR9. Based on the responses elicited by exposure of MG to reproductive tract epithelial cells, we next tested and determined that MG was susceptible to killing by human and murine macrophages. Importantly, we then showed that intracellular localization within epithelial cells provided MG a survival niche against macrophage-mediated killing thereby providing a mechanism for evasion of the host immune response. Considering the ability of MG to exploit long-term intracellular survival within epithelial cells, we next developed a murine model of reproductive tract infection to investigate how MG establishes infection and how intact mucosa respond to MG exposure. Similar to cultured human epithelial cells, vaginal lavages of MG-inoculated mice showed significant pro-inflammatory cytokine responses. Concomitantly, we observed intermittent vaginal shedding for up 77d PI indicating that MG is capable of long-term reproductive tract infection. Most importantly, we also determined that MG rapidly ascended to the upper reproductive tract tissues and disseminated to the knee joints following vaginal exposure. These findings were the first experimental evidence for dissemination of MG to the upper reproductive tract and provided excellent rationale for continued investigation into the capacity of MG to cause reproductive tract disease. Collectively, our results indicate that MG has the capacity to elicit reproductive tract inflammation and should heighten awareness for this emerging pathogen.